Currently, as thrombosis inhibitors, antithrombin agents are employed. The antithrombin agents exhibit, together with the anticoagulation activity for blood, an inhibiting activity against the platelet-coagulation effect of thrombin. Therefore, it is known that the antithrombin agents may exhibit a tendency to promote bleeding, and thus the control of the inhibiting effect the conventional thrombin agents against the blood coagulation is not easy.
In view of the above-mentioned prior art, it is now attempted to develop a new blood coagulation-inhibiting agent on a basis of an activation mechanism different from that of the blood coagulation-inhibiting activity of the conventional thrombin agents. For example, WO 99/26918 discloses biphenylamidine derivatives having an anti blood-coagulation activity.
As a method of synthesizing a compound having a biphenyl skeleton and useful as an intermediate of the biphenylamidine derivative useful as an FXa inhibitor, WO 99/26918 discloses a method comprising preparing 3-cyanophenylboronic acid from 3-bromobenzonitrile and subjecting the 3-cyanophenylboronic acid to a coupling reaction with 3-iodo-3-(hydroxymethyl)benzoic acid compound, to provide a 5-(3-cyanophenyl)-3-hydroxymethylbenzoic acid compound. This method, however is industrially disadvantageous in that the synthesis of 3-cyanophenylboronic acid needs a reaction at an extremely low temperature of −78° C., and this extremely low temperature reaction is difficult to effect in industrial practice, that the coupling reaction needs to employ an iodine compound which is expensive, and that the resultant target compound must be purified by using a column chromatography which is difficult to use in industrial practice. Further, each reaction step of the above-mentioned method has problems which are difficult to solve.
As a synthesis method of a phenylboronic acid compound, a method in which a halogenated benzene derivative is converted to an organic metal compound of the derivative and then the organic metal compound reacts with a trialkyl borate, is known from, for example, “The Chemistry of Boron”, Academic, New York, 1961; “Methods of Elemento-Organic Chemistry, North-Holland, Amsterdam, 1976, Vol. 1; “Organoborane Chemistry”, Academic, New York, 1975, etc.
In the above-mentioned method using the organic metal compound in the case where the organic metal compound is a lithium compound, the reaction of the lithium compound with the trialkyl borate must be conducted at an extremely low temperature of −78° C. Also, in the case where the organic metal compound is a Grignard reagent and in the case where the halogenated benzene derivative has, as a substituent group, a cyano group, it is difficult to prepare a boronic acid compound from the Grignard reagent.
Also, Japanese Unexamined Patent Publication No. 7-17937 discloses a method of selectively reducing only one of two ester groups in an aromatic diester compound. However, this method is disadvantageous in that when this method is utilized to synthesize 5-bromo-3-hydroxymethylbenzoric acid derivative from a 5-bromoisophthalic acid derivative, a side reaction by which both the ester groups of the isophthalate diester are reduced to produce, as a by-product, 5-bromo-3-hydroxymethylbenzyl alcohol in a yield of about 10 molar %, occurs. To remove the by-product, a product of any one of the succeeding procedures must be subjected to a column chromatography which is difficult to be conducted in industrial practice.
The coupling reaction of the boronic acid compound with a halogenated aromatic compound is generally known as a SUZUKI coupling reaction. (Referential documents: Acvavces in Metal-Organic Chemistry, JAI Press Inc, Vol. 6, page 187-243, Organic Lettes., Vol. 1, No. 7, page 965-967 (1999), etc.). With respect to this coupling reaction, WO 00/69811 discloses that the employment of tetrabutylammonium bromide causes the reaction to be completed within a short time. However, a new method enabling the efficiency of the coupling reaction to be enhanced without using the tetrabutylammonium bromide, is desired.
Various methods of oxidizing the aromatic compound having a hydroxymethyl group with manganese dioxide, which is cheap, in a reaction medium comprising methylene chloride, to convert the hydroxymethyl group to a formyl group are known. (Referential documents: Polish J. Chem., 53, 1889 (1975) and Lectures of Experimental Chemistry, Vol. 23, page 21.) These conventional methods are disadvantageous in that the employment of methylene chloride having a low boiling temperature causes a recovery of methylene chloride to be difficult and methylene chloride is harmful to the human body. Accordingly, it is desired to develop a new method in which a reaction medium different from methylene chloride and free from the above-mentioned disadvantages is employed in place of methylene chloride.